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Biomedical subjects

M A Creager

Publications and source records attributed to M A Creager.

At least 55 records · Page 3Linked to original sources
PubMed1996

Importance of findings on the initial evaluation for cancer in patients with symptomatic idiopathic deep venous thrombosis.

BACKGROUND: The relation between thrombosis and cancer is well documented, but the clinical evaluation appropriate for detecting underlying cancer in patients with deep venous thrombosis remains unknown. OBJECTIVES: To 1) determine the appropriate initial evaluation for cancer in patients with idiopathic deep venous thrombosis and 2) estimate the incidence of subsequently diagnosed cancer in patients who were not found to have cancer when deep venous thrombosis was diagnosed. DESIGN: Retrospective cohort study. SETTING: Urban, tertiary care teaching hospital. PATIENTS: 986 consecutive patients (637 women and 349 men; mean age +/- SD, 53 +/- 17 years) who had no risk factors for venous disease and had venous ultrasonography because idiopathic deep venous thrombosis was suspected. MEASUREMENTS: Initial clinical evaluation was assessed by using chart review. The incidence of cancer at a median of 34 months after diagnosis of deep venous thrombosis was obtained through hospital chart review (38%), computerized record extraction (54%), mailed questionnaires (6%), telephone interviews (1%), or a death registry (1%). RESULTS: Deep venous thrombosis was diagnosed in 142 patients (14%); 136 of the 142 were hospitalized. Cancer was diagnosed in 16 of these 136 patients (12%) during the index hospitalization. All 16 of these patients had one or more abnormalities on at least one of the four components of the clinical examination: history, physical examination, basic laboratory testing, or chest radiography. The probability of detecting cancer increased as the number of findings suggestive of cancer on the four components of the clinical evaluation increased. Cancer was diagnosed in none of the 56 patients with deep venous thrombosis who did not have findings on the clinical evaluation. The probability of cancer-free survival during follow-up (median, 34 months) was similar in patients with (3 of 122 [2.5%]) and without (23 of 844 [2.7%]) deep venous thrombosis and in the age- and sex-matched U.S. population. CONCLUSIONS: A clinical evaluation that includes a comprehensive medical history, physical examination, routine laboratory testing, and chest radiography seems to be appropriate for detecting cancer in these patients. Additional testing should be guided by any abnormalities detected by this clinical evaluation.

Adult↗
PubMed1996

Pathogenic mechanisms of atherosclerosis: effect of lipid lowering on the biology of atherosclerosis.

Numerous trials have demonstrated that cholesterol-lowering therapy leads to marked reductions in cardiovascular and overall mortality and in the need for coronary revascularization. Angiographic regression trials have shown that cholesterol lowering can reduce progression and, in some instances, achieve regression of coronary atherosclerotic lesions. However, recent studies have contradicted the traditional view that the clinical course of coronary artery disease is closely linked to the severity of coronary artery stenosis. It is now apparent that stenoses responsible for myocardial infarction or unstable angina are typically mild rather than severe. These observations suggest that regression may not be the principal mechanism by which cholesterol lowering affects cardiovascular risk. Two mechanisms---plaque stabilization and improved endothelial function-have been examined in this regard. Basic studies suggest that cholesterol lowering favorably alters those features of atherosclerosis that promote plaque stability. Recent clinical studies have clearly established that aggressive lipid-lowering therapy improves endothelial function and reduces myocardial ischemia in patients with hypercholesterolemia.

Acetylcholine↗
PubMed1996

Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus.

OBJECTIVES: This study sought to determine whether nitric oxide-mediated vasodilation is abnormal in patients with non-insulin-dependent diabetes mellitus. BACKGROUND: Multiple investigations, both in experimental models and in patients with insulin-dependent diabetes mellitus, demonstrate impaired endothelium-dependent vasodilation. Decreased availability of endothelium-derived nitric oxide may contribute to the high prevalence of vascular disease in diabetes. METHODS: Vascular reactivity was measured in the forearm resistance vessels of 21 patients with non-insulin-dependent diabetes mellitus and 23 matched healthy control subjects. No patient had hypertension or hypercholesterolemia. Each subject was pretreated with aspirin to inhibit endogenous production of vasoactive prostanoids. Methacholine chloride (0.3 to 10 microg/min) was administered through a brachial artery cannula to assess vasodilation to endothelium-derived nitric oxide. Sodium nitroprusside (0.3 to 10 microg/min) was infused to evaluate vasodilation to an exogenous nitric oxide donor. Verapamil (10 to 300 microg/min) was administered to distinguish impaired nitric-oxide-mediated vasodilation from general dysfunction of vascular smooth muscle. Forearm blood flow was determined by venous occlusion plethysmography, and dose-response curves were generated for each agent. To assess the role of vasoconstrictor prostanoids, a subset of eight diabetic subjects were reexamined in the absence of aspirin treatment. RESULTS: Basal forearm blood flow in diabetic and nondiabetic subjects was comparable. The forearm blood flow responses to both methacholine chloride and nitroprusside were significantly attenuated in diabetic compared with nondiabetic subjects (p < 0.005 by analysis of variance for both agents). In contrast, the response to verapamil was not significantly different between the groups (p > 0.50). The forearm blood flow responses to these agents were not significantly affected by cyclooxygenase inhibition. CONCLUSIONS: Nitric oxide-mediated vasodilation is impaired in non-insulin-dependent diabetes mellitus. Vasoconstrictor prostanoids do not contribute significantly to vascular dysfunction. The attenuated response to exogenous as well as endogenous nitric oxide donors suggests that the abnormality is due to increased inactivation of nitric oxide or to decreased reactivity of the vascular smooth muscle to nitric oxide.

Adult↗
PubMed1996

Role of nitric oxide in the local regulation of pulmonary vascular resistance in humans.

BACKGROUND: Endothelium-derived nitric oxide (NO) may be an important mediator of vascular resistance in the pulmonary circulation. We tested the hypotheses that in conscious adults the endothelium, through NO production, is important in maintaining basal pulmonary vascular resistance and that it can increase NO production further in response to receptor-mediated stimulation, leading to further vasodilation. METHODS AND RESULTS: Pulmonary arterial resistance vessel function was studied within the distribution of a segmental lower lobe pulmonary artery in eight conscious adults 37 to 76 years old who were undergoing cardiac catheterization. Segmental blood flow was determined with use of a Doppler-tip guide wire and quantitative angiography. Drugs were administered locally within the segmental artery through an infusion catheter. NG-Monomethyl-L-arginine (L-NMMA) was used as a specific inhibitor of NO production, whereas acetylcholine (ACh) was used to test receptor-mediated vasodilation. To demonstrate that vasodilation to ACh was NO dependent, ACh response was tested alone, in the presence of L-NMMA, and in the presence of a control constrictor phenylephrine. Basal pulmonary vascular resistance was NO dependent because L-NMMA infusion resulted in a dose-dependent decrease in local flow velocity (P < .005), with flow decreasing 33% at the highest dose of L-NMMA. ACh infusion resulted in a dose-dependent increase in flow velocity (P = .001). The ACh response was at least in part NO dependent because it was diminished by the presence of L-NMMA (P < .05). The effect of L-NMMA on the ACh response was not due to nonspecific preconstriction because L-NMMA diminished the ACh response significantly more than did the endothelium-independent constrictor phenylephrine (P < .05) despite comparable preconstriction. CONCLUSIONS: In healthy conscious adults, (1) normal basal pulmonary resistance is maintained in part by continuous local production of NO and (2) the local NO production is responsive to receptor-mediated stimulation, leading to further vasodilation, and can be tested with ACh.

Acetylcholine↗
PubMed1996

Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus.

Endothelium-dependent vasodilation is impaired in humans with diabetes mellitus. Inactivation of endothelium-derived nitric oxide by oxygen-derived free radicals contributes to abnormal vascular reactivity in experimental models of diabetes. To determine whether this observation is relevant to humans, we tested the hypothesis that the antioxidant, vitamin C, could improve endothelium-dependent vasodilation in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus. We studied 10 diabetic subjects and 10 age-matched, nondiabetic control subjects. Forearm blood flow was determined by venous occlusion plethysmography. Endothelium-dependent vasodilation was assessed by intraarterial infusion of methacholine (0.3-10 micrograms/min). Endothelium-independent vasodilation was measured by intraarterial infusion of nitroprusside (0.3-10 micrograms/min) and verapamil (10-300 micrograms/min). Forearm blood flow dose-response curves were determined for each drug before and during concomitant intraarterial administration of vitamin C (24 mg/min). In diabetic subjects, endothelium-dependent vasodilation to methacholine was augmented by simultaneous infusion of vitamin C (P = 0.002); in contrast, endothelium-independent vasodilation to nitroprusside and to verapamil were not affected by concomitant infusion of vitamin C (P = 0.9 and P = 0.4, respectively). In nondiabetic subjects, vitamin C administration did not alter endothelium-dependent vasodilation (P = 0.8). We conclude that endothelial dysfunction in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus can be improved by administration of the antioxidant, vitamin C. These findings support the hypothesis that nitric oxide inactivation by oxygen-derived free radicals contributes to abnormal vascular reactivity in diabetes.

Adult↗
PubMed1996

Endothelium-derived nitric oxide regulates systemic and pulmonary vascular resistance during acute hypoxia in humans.

OBJECTIVES: This investigation sought to determine whether endothelium-derived nitric oxide contributes to hypoxia-induced systemic vasodilation and pulmonary vasoconstriction in humans. BACKGROUND: Endothelium-derived nitric oxide contributes to basal systemic and pulmonary vascular resistance. During hypoxia, systemic vasodilation and pulmonary vasoconstriction occur. There are some data indicating that endothelium-derived nitric oxide mediates changes in vascular resistance during hypoxia, but much of it is contradictory, and none has been derived from normal humans. METHODS: The hemodynamic effects of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor, were studied in healthy volunteers under normoxic and hypoxic conditions. A Swan-Ganz catheter and radial artery cannula were inserted to measure right atrial, pulmonary artery, pulmonary capillary wedge and systemic blood pressures. Cardiac output was measured by thermodilution. Systemic vascular resistance and pulmonary vascular resistance were calculated. The pharmacokinetics of L-NMMA (300 mg intravenously) was studied during normoxia in six subjects. Hypoxia was induced in eight subjects who inspired a mixture of nitrogen and oxygen through a gas blender adjusted to reduce the partial pressure of oxygen from (mean +/- SE) 98 +/- 4 to 48 +/- 1 mm Hg. RESULTS: During normoxia, L-NMMA increased systemic vascular resistance from 1,108 +/- 74 to 1,705 +/- 87 dynes-s-cm-5 and increased pulmonary vascular resistance from 60 +/- 5 to 115 +/- 9 dynes-s-cm-5 (p < or = 0.01 for each). Peak effects occurred within 10 min of L-NMMA administration. Acute hypoxia alone decreased systemic vascular resistance from 1,209 +/- 78 to 992 +/- 58 dynes-s-cm-5 (p < or = 0.05) and increased pulmonary vascular resistance from 92 +/- 11 to 136 +/- 4 dynes-s-cm-5 (p < or = 0.01). While hypoxic conditions were maintained, infusion of L-NMMA increased systemic vascular resistance (to 1,496 +/- 97 dynes-s-cm-5, p < or = 0.01) and increased pulmonary vascular resistance further (to 217 +/- 25 dynes-s-cm-5, p < or = 0.01). CONCLUSIONS: Endothelium-derived nitric oxide contributes to systemic vasodilation and serves as a counterregulatory mechanism to attenuate pulmonary vasoconstriction during acute hypoxia in healthy human subjects.

Acute Disease↗
PubMed1996

Bolus recombinant urokinase versus heparin in deep venous thrombosis: a randomized controlled trial.

Bolus urokinase (Abbokinase ) is effective for initial treatment of deep venous thrombosis but is associated with a high rate of rigors. This randomized controlled trial was undertaken among patients with deep venous thrombosis to evaluate the efficacy and safety of a novel thrombolytic agent, recombinant urokinase (rUK), administered as three bolus infusions of 1 million U over a 24-hour period versus heparin alone. Of 361 patients with DVT screened, 17 (5%) were enrolled. Recent surgery was the most common reason for exclusion (n = 113, 31%). Images of the patients were obtained at baseline, 24 to 48 hours after randomization, and before hospital discharge. Two patients in each treatment group had minor clot progression. One patient in the heparin group had no change; all other patients showed mild (< 50%; n = 5 in each group) or moderate (> 50%; n = 1 in each group) improvement. No bleeding complications or rigors developed in patients randomized to rUK. Mean bleeding times among patients given rUK were not significantly different from mean values of patients given heparin at any of the measured time points available for comparison (331 vs 387 seconds at baseline and 381 vs 416 seconds at 24 hours). However, mean fibrinogen levels declined with successive urokinase boluses and were significantly lower than levels in patients treated with heparin at 24 (233 mg/dl vs 466 mg/dl, p = 0.01) and 48 hours (270 mg/dl vs 474 mg/dl, p = 0.02). Although bolus rUK had a favorable safety profile, rUK was no more effective than heparin in achieving clot lysis at the doses used in this trial.

Adult↗
PubMed1996

Biological mechanisms for the clinical success of lipid-lowering in coronary artery disease and the use of surrogate end-points.

The small changes in luminal narrowing observed with lowering total cholesterol are unlikely to be the principal mechanism by which lipid-lowering achieves a reduction in clinical events and revascularization rates. Endothelium dependent vasomotor function, and the cellular characteristics of plaques that seem to be intimately related to rupture and thrombosis, are factors that may explain the clinical success from correcting the dyslipidemias. Dyslipidemias cause endothelial dysfunction that predisposes to vasoconstriction of the epicardial coronary arteries and the resistance vessels relative to metabolic demand. Dysfunctional endothelium also promotes the recruitment of inflammatory cells into the vessel wall which contributes to the activation of vascular smooth muscle cells and sets up an environment within the plaque that predisposes to rupture and a prothrombotic state. Aggressive lowering of total cholesterol, and especially LDL and oxidized LDL, improves coronary endothelial function both of the epicardial and resistance vessels, and leads to a reduction in myocardial ischemia. Lipid-lowering may promote plaque stability in part by reducing the recruitment of inflammatory cells, and possibly by changing the size or consistency of the lipid-rich core of plaques. A thicker fibrous cap and stiffer plaque that is less likely to rupture may result, and in the event that rupture does occur, cholesterol lowering may reduce the formation of overlying thrombus. Testing coronary or peripheral artery endothelial vasomotor dysfunction may be a surrogate measure for assessing the effectiveness of interventions to prevent coronary heart disease. These tests are likely to be used increasingly to identify interventions that deserve greater attention in larger clinical trials, as well as providing mechanisms for any observed clinical benefits.

Animals↗
PubMed1996

Postischemic vasodilation in human forearm is dependent on endothelium-derived nitric oxide.

Although endothelium-derived nitric oxide contributes to basal vascular tone, little is known about its role in regulating blood flow during changes in metabolic supply and demand. We examined the contribution of endothelium-derived nitric oxide to reactive hyperemia in the forearm of 20 normal subjects (12 women, 8 men) aged 27 +/- 4 yr (means +/- SD), using the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA). Forearm ischemia was induced by suprasystolic blood pressure cuff inflation for 5 min, and the subsequent hyperemic flow was recorded for 5 min using venous occlusion strain-gauge plethysmography. The efficacy of nitric oxide blockade was tested by comparing the dose-response relationship to the endothelium-dependent agonist, acetylcholine (3, 10, and 30 mg/min), before and after intra-arterial infusion of up to 2,000 mg/min of L-NMMA. L-NMMA produced a significant downward and rightward shift in the dose-response relationship to acetylcholine and a 39% reduction in response to the maximum dose (P < 0.001). In the presence of L-NMMA, peak hyperemic flow was reduced 16% (26.5 +/- 2.1 to 22.3 +/- 1.5 ml.min-1.100 ml of forearm-1, P < 0.03), and the minimum forearm vascular resistance was increased 22.8% (3.5 +/- 0.3 to 4.3 +/- 0.4 mmHg.ml-1.min.100 ml, P < 0.02). Total hyperemia, calculated from the area under the flow vs. time curve, at 1 and 5 min after cuff release was 17 and 23% less, respectively (13.6 +/- 1.2 vs. 11.3 +/- 1.1 and 31.8 +/- 2.7 vs. 24.6 +/- 1.8 ml/100 ml, P < 0.002), following L-NMMA. These data suggest that endothelium-derived nitric oxide plays a role in both reactive hyperemia and in the maintenance of the hyperemic response following ischemia in the forearm.

Acetylcholine↗
PubMed1996

Endothelium-derived nitric oxide mediates hypoxic vasodilation of resistance vessels in humans.

Endothelium-derived nitric oxide (EDNO) contributes to basal systemic vascular resistance under normoxic conditions. The purpose of this investigation was to determine whether EDNO contributes to the regulation of limb vascular resistance during hypoxia in healthy humans. Forearm blood flow was assessed by venous occlusion plethysmography. Hypoxia was induced by delivering a mixture of N2 and O2 via a gas blender adjusted to reduce the PO2 to 50 mmHg. During hypoxia, forearm blood flow increased from 2.4 +/- 0.2 to 3.0 +/- 0.3 ml.100 ml-1.min-1 (P < 0.001), and forearm vascular resistance decreased from 38 +/- 3 to 29 +/- 3 units (P < 0.001). The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 2,000 micrograms/min intra-arterially) was administered to eight subjects. The percent increase in forearm vascular resistance after administration of L-NMMA was greater during hypoxia than normoxia (67 +/- 14 vs. 39 +/- 15%, P < 0.05). L-NMMA reduced the forearm vasodilator response to hypoxia from 27 +/- 3 to 11 +/- 5% (P = 0.01). To exclude the possibility that this attenuated response to hypoxia was a consequence of vasoconstriction and not specific for nitric oxide synthase inhibition, six subjects received intra-arterial phenylephrine. Phenylephrine did not affect the vasodilator response to hypoxia (17 +/- 3 vs. 21 +/- 6%, P = NS). It is concluded that EDNO contributes to hypoxia-induced vasodilation in the forearm resistance vessels in healthy humans.

Adult↗
PubMed1996

Activation of ATP-sensitive potassium channels contributes to reactive hyperemia in humans.

Activation of ATP-sensitive potassium (KATP) channels present on vascular smooth muscle cells causes membrane hyperpolarization and vasodilation. The purpose of this study was to determine whether KATP channels contribute to reactive hyperemia in humans. Accordingly, we studied the effect of tolbutamide, a KATP channel inhibitor, on reactive hyperemic forearm blood flow. Forearm blood flow was measured by venous occlusion plethysmography. Forearm ischemia was produced by inflating a sphygmomanometric cuff on the arm to suprasystolic pressures for 5 min. After cuff release, forearm blood flow was measured during the reactive hyperemic phase for 5 min. Tolbutamide (1 mM blood concentration, n = 6) did not affect basal (2.4 +/- 0.2 to 2.2 +/- 0.1 ml.100 ml-1.min-1) or peak reactive hyperemic forearm blood flow (21.9 +/- 3.8 to 22.6 +/- 2.9 ml.100 ml-1.min-1, each P = NS), but it significantly attenuated total hyperemic volume (12.6 +/- 1.7 vs. 9.2 +/- 1.8 ml/100 ml, P < 0.02). Vehicle (n = 6) did not affect basal flow, peak reactive hyperemic flow, or total hyperemia. To determine whether adenosine or endothelium-derived nitric oxide contribute to reactive hyperemia via KATP channels, adenosine (1.5-500 micro grams/min, n = 6) and acetylcholine (30 micrograms/min, n = 6) were infused before and during tolbutamide coinfusion. Tolbutamide did not significantly alter the forearm blood flow response to either adenosine or acetylcholine. In conclusion, KATP channels contribute to vasodilation during reactive hyperemia in humans.

Acetylcholine↗
PubMed1996

Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans.

Studies in experimental models suggest that endothelium-derived nitric oxide is reduced with aging, and this circumstance may be relevant to atherogenesis. The aim of this study was to determine whether increasing age resulted in altered endothelium-dependent vasodilation in the forearm resistance vessels of healthy humans. Forearm blood flow was measured in 119 healthy subjects, aged 19 to 69 years, by venous occlusion plethysmography. Brachial artery infusions of methacholine chloride (0.03 to 10.0 microgram/min) were used to assess endothelium-dependent vasodilation and of sodium nitroprusside (0.03 to 10.0 microgram/min) to assess endothelium-independent vasodilation. The slope of the dose-blood flow response relation was calculated in each subject for each drug. Univariate and multiple stepwise regression analyses were used to relate vascular reactivity to selected variables, including age, lipids, and blood pressure. Endothelium-dependent vasodilation was progressively impaired with increasing age, assessed as a reduction in slope from 2.25 +/- 0.16 to 0.34 +/- 0.11 (mL/100 mL tissue per minute)/(microgram/min) (P <.001). The decline in endothelium-dependent vasodilation was already evident by the fourth decade (age 30 to 39 years). Endothelium-independent vasodilation did not change with age. Age, total cholesterol, and low-density lipoprotein cholesterol were univariate predictors of endothelium-dependent vasodilation. Age remained the most significant predictor of endothelium-dependent vasodilator responses by multiple stepwise regression analysis. From these observations, it can be concluded that endothelium-dependent vasodilation declines steadily with increasing age in healthy human subjects. Age is a strong univariate and multivariate predictor of endothelium-dependent vasodilation. This finding may be a marker for more widespread endothelial dysfunction.

Adult↗
PubMed1995

Prevention of venous thrombosis after coronary artery bypass surgery (a randomized trial comparing two mechanical prophylaxis strategies).

Although venous thrombosis may occur often after coronary artery bypass grafting, prophylaxis with low-dose heparin is rarely used due to the risk of bleeding. Therefore, we compared the efficacy of 2 mechanical regimens of prophylaxis against deep vein thrombosis (DVT). Consecutive patients undergoing coronary artery bypass without concomitant valve surgery or coronary endarterectomy were randomized to either a more intensive regimen of intermittent pneumatic compression (IPC) plus graduated compression stockings (GCS) versus standard compression stockings alone. Of 611 patients screened, 184 were excluded due to peripheral vascular disease, postoperative intraaortic balloon support, or immediate postoperative anticoagulation. An additional 83 patients refused consent, leaving 172 in each prophylaxis group. The primary study end point was DVT diagnosed by a predischarge leg ultrasound examination performed on postoperative days 4 to 6. Of 344 patients enrolled, 330 (96%) underwent predischarge ultrasonography. DVT was detected in 19% of patients assigned to IPC plus stockings versus 22% assigned to GCS alone (95% confidence interval for the difference, -11% to 6%, p = 0.62). The addition of IPC did not add significant incremental benefit to GCS alone for DVT prophylaxis among patients undergoing coronary artery bypass surgery.

Aged↗
PubMed1995

Close relation of endothelial function in the human coronary and peripheral circulations.

OBJECTIVES: The relation between endothelium-dependent vasodilator function in the brachial and coronary arteries was determined in the same subjects. BACKGROUND: Coronary artery endothelial dysfunction precedes the development of overt atherosclerosis and is important in its pathogenesis. A noninvasive assessment of endothelial function in a peripheral conduit vessel, the brachial artery, was recently described, but the relation between brachial artery function and coronary artery vasodilator function has not been explored. METHODS: In 50 patients referred to the catheterization laboratory for the evaluation of coronary artery disease (mean age +/- SD 56 +/- 10 years), the coronary vasomotor response to serial intracoronary infusions of the endothelium-dependent agonist acetylcholine (10(-8) to 10(-6) mol/liter), was studied. Endothelium-dependent vasodilation was also assessed in the brachial artery by measuring the change in brachial artery diameter in response to reactive hyperemia. RESULTS: Patients with coronary artery endothelial dysfunction manifested as vasoconstriction in response to acetylcholine had significantly impaired flow-mediated vasodilation in the brachial artery compared with that of patients with normal coronary endothelial function (4.8 +/- 5.5% vs. 10.8 +/- 7.6%, p < 0.01). Patients with coronary artery disease also had an attenuated brachial artery vasodilator response compared with that of patients with angiographically smooth coronary arteries (4.5 +/- 4.6% vs. 9.7 +/- 8.1%, p < 0.02). By multivariate analysis, the strongest predictors of reduced brachial dilator responses to flow were baseline brachial artery diameter (p < 0.001), coronary endothelial dysfunction (p = 0.003), the presence of coronary artery disease (p = 0.007) and cigarette smoking (p = 0.016). The brachial artery vasodilator response to sublingual nitroglycerin was independent of coronary endothelial responses or the presence of coronary artery disease. The positive predictive value of abnormal brachial dilation ( < 3%) in predicting coronary endothelial dysfunction is 95%. CONCLUSIONS: This study demonstrated a close relation between coronary artery endothelium-dependent vasomotor responses to acetylcholine and flow-mediated vasodilation in the brachial artery. This noninvasive method may become a useful surrogate in assessing the predisposition to atherosclerosis in patients with cardiac risk factors.

Acetylcholine↗
PubMed1995

Endothelial release of nitric oxide contributes to the vasodilator effect of adenosine in humans.

BACKGROUND: The endogenous nucleoside adenosine plays an important role in the regulation of vascular tone, especially during ischemia. Experimental data derived from animal models suggest that nitric oxide (NO) contributes to the vasodilator effect of adenosine. The primary purpose of this investigation was to determine whether the endothelial release of NO contributes to adenosine-induced vasodilation in humans. METHODS AND RESULTS: Venous occlusion plethysmography was used to assess the forearm blood flow (FBF) responses to graded intra-arterial infusions of adenosine (1.5 to 500 micrograms/min). Dose-response curves were constructed before and during intra-arterial infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) (2 mg/min, n = 6) or vehicle (n = 6). Before infusion of L-NMMA, adenosine caused a dose-dependent increase in FBF from 2.3 to 15.9 mL.min-1.dL-1. During concurrent infusion of L-NMMA, adenosine increased FBF from 1.7 to 10.0 mL.min-1.dL-1, and this change from baseline was significantly reduced compared with that before L-NMMA (P < .05). L-NMMA also attenuated the FBF response to adenosine when the basal constrictor effect of L-NMMA was prevented by coinfusion of the NO donor sodium nitroprusside (n = 6, P < .01). In contrast, L-NMMA did not affect the FBF response to intra-arterial infusion of the endothelium-independent vasodilator verapamil (from 2.0 to 13.9 mL.min-1.dL-1 before L-NMMA and from 1.3 to 13.6 mL.min-1.dL-1 during L-NMMA; n = 6, P = NS). The second objective of this study was to determine whether the adenosine-induced release of NO is mediated by activation of endothelial potassium channels, putatively coupled to adenosine receptors. Thus, the FBF response to adenosine was measured before and during infusion of the ATP-dependent potassium channel blocker tolbutamide (1 mg/min, n = 6), or the potassium channel blocker quinidine (0.5 mg/min, n = 6). The adenosine-mediated increments in FBF were not attenuated by either potassium channel blocker. CONCLUSIONS: Adenosine-induced vasodilation in humans is mediated, at least in part, by endothelial release of NO. The transducing mechanism of this phenomenon is not known, but it does not appear to involve the activation of either ATP-dependent or quinidine-sensitive potassium channels.

Adenosine↗
PubMed1995

Nitric oxide inhibits the positive inotropic response to beta-adrenergic stimulation in humans with left ventricular dysfunction.

BACKGROUND: Nitric oxide (NO) attenuates the contractile response to beta-adrenergic stimulation in cultured cardiac myocytes in vitro and in myocardium in vivo. We tested the hypothesis that NO synthesized in the heart inhibits the positive inotropic response to beta-adrenergic stimulation in humans with left ventricular (LV) dysfunction. METHODS AND RESULTS: Patients with various degrees of LV dysfunction and free from epicardial coronary artery disease were instrumented with an infusion catheter in the left main coronary artery and a high-fidelity micromanometer-tipped catheter in the LV. Measurements included LV pressure, aortic pressure, heart rate, and LV peak +dP/dt. In eight subjects, dobutamine was infused via the left main coronary artery (25 or 50 micrograms/min) before and concurrent with intracoronary infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 20 mumol/min for 10 minutes). In six other subjects, dobutamine was infused (6, 10, or 15 micrograms.kg-1.min-1) via a peripheral vein. Intracoronary (n = 8) dobutamine infusions increased LV peak +dP/dt by an average of 33 +/- 3%. The intracoronary infusion of L-NMMA had no effect on baseline LV peak +dP/dt, LV systolic or end-diastolic pressures, aortic pressure, or heart rate. The intracoronary infusion of L-NMMA, concurrent with a second infusion of dobutamine, potentiated the +dP/dt response to dobutamine by 30 +/- 10% (P < .04 versus dobutamine alone). The intracoronary infusion of L-NMMA likewise potentiated the +dP/dt response to the peripheral infusion of dobutamine by 37 +/- 18%. CONCLUSIONS: Nitric oxide produced in the heart attenuates the positive inotropic response to beta-adrenergic stimulation in humans with LV dysfunction. NO may contribute to beta-adrenergic hyporesponsiveness in patients with LV dysfunction.

Adrenergic beta-Agonists↗